TY  - JOUR
A1  - Klingseisen, Laura
A1  - Ehrenschwender, Martin
A1  - Heigl, Ulrike
A1  - Wajant, Harald
A1  - Hehlgans, Thomas
A1  - Schütze, Stefan
A1  - Schneider-Brachert, Wulf
T1  - E3-14.7K Is Recruited to TNF-Receptor 1 and Blocks TNF Cytolysis Independent from Interaction with Optineurin
T2  - PLoS One
N2  - Escape from the host immune system is essential for intracellular pathogens. The adenoviral protein E3-14.7K (14.7K) is known as a general inhibitor of tumor necrosis factor (TNF)-induced apoptosis. It efficiently blocks TNF-receptor 1 (TNFR1) internalization but the underlying molecular mechanism still remains elusive. Direct interaction of 14.7K and/or associated proteins with the TNFR1 complex has been discussed although to date not proven. In our study, we provide for the first time evidence for recruitment of 14.7K and the 14.7K interacting protein optineurin to TNFR1. Various functions have been implicated for optineurin such as regulation of receptor endocytosis, vesicle trafficking, regulation of the nuclear factor kappa B (NF-kappa B) pathway and antiviral signaling. We therefore hypothesized that binding of optineurin to 14.7K and recruitment of both proteins to the TNFR1 complex is essential for protection against TNF-induced cytotoxic effects. To precisely dissect the individual role of 14.7K and optineurin, we generated and characterized a 14.7K mutant that does not confer TNF-resistance but is still able to interact with optineurin. In H1299 and KB cells expressing 14.7K wild-type protein, neither decrease in cell viability nor cleavage of caspases was observed upon stimulation with TNF. In sharp contrast, cells expressing the non-protective mutant of 14.7K displayed reduced viability and cleavage of initiator and effector caspases upon TNF treatment, indicating ongoing apoptotic cell death. Knockdown of optineurin in 14.7K expressing cells did not alter the protective effect as measured by cell viability and caspase activation. Taken together, we conclude that optineurin despite its substantial role in vesicular trafficking, endocytosis of cell surface receptors and recruitment to the TNFR1 complex is dispensable for the 14.7K-mediated protection against TNF-induced apoptosis.
KW  - 14.7K
KW  - tumor necrosis factor
KW  - NF-kappa-B
KW  - E3 14.7-kilodalton protein
KW  - myosin-VI
KW  - apoptosis
KW  - cells
KW  - compartmentalization
KW  - inhibitor
KW  - binding
Y1  - 2012
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/13568
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-135687
VL  - 7
IS  - 6
ER  -